Objective Our aim is to seek detailed molecular level understanding of the interactions between HIV-1 and innate immune sensors expressed in myeloid cells. We have demonstrated that HIV-1 replicates in primary human macrophages without triggering interferon production. However, by specific mutation of HIV-1 proteins or by manipulating interaction with host cofactors we can reveal the virus to innate immune receptors and activate an antiviral response leading to secretion of soluble type 1 interferon and cessation of replication. We propose to define the sensors and the details of the antiviral pathways that are activated in macrophages using proven RNA interference techniques reading out activation of innate immune responses by measurement of secreted interferon and induction of gene expression. We have also characterised small molecules that potently inhibit HIV-1 by revealing HIV-1 to innate immune sensors. In collaboration with crystallographers and medicinal chemists we aim to improve the potency and specificity of these drugs and to use them to study the anti-HIV-1 innate immune response. DC are sentinels of innate immunity and their infection induced maturation leads to interferon production and DC dependent T cell maturation that defines the nature and potency of the immune response. We will examine the effect of triggering innate responses in DC using HIV-1 mutants/drug treated wild type virus on allogeneic responses, by measurement of T cell proliferation and function and in an ex vivo CD8 T cell killing assays using peripheral blood CD8 cells from HIV‑1 infected patients. In this way we will uncover the molecular details of HIV-1’s interaction with innate immunity and discover how the virus replicates in primary immune cells without detection. This work will make a significant technical and intellectual contribution to an important emerging scientific field focusing on understanding and manipulating the complex relationship between HIV-1 and innate immunity. Fields of science natural sciencesbiological sciencesmicrobiologyvirologymedical and health sciencesbasic medicineimmunologymedical and health scienceshealth sciencesinfectious diseasesRNA virusesHIVengineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensorsmedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS6 - ERC Advanced Grant - Immunity and infection Call for proposal ERC-2013-ADG See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Coordinator UNIVERSITY COLLEGE LONDON EU contribution € 2 499 643,00 Address Gower street WC1E 6BT London See on map Activity type Higher or Secondary Education Establishments Principal investigator Gregory John Towers (Prof.) Administrative Contact Giles Machell (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all UNIVERSITY COLLEGE LONDON EU contribution € 2 499 643,00 Address Gower street WC1E 6BT London See on map Activity type Higher or Secondary Education Establishments Principal investigator Gregory John Towers (Prof.) Administrative Contact Giles Machell (Mr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data